The Mouse That Heard

Ann Arbor, MI (5/14/98)- A successful genetic repair
job that restored hearing to the offspring of congenitally deaf mice could
offer a new gene-therapy strategy for preventing deafness in humans.

Researchers at the University of Michigan first used transgenic technology
to find the recessive mutated gene responsible for deafness in shaker-2
mice. This strain of mouse carries an X-ray induced mutation that causes
deafness. The investigators then injected short sections of normal cloned
DNA into fertilized mouse eggs to see which DNA clone would produce a hearing
mouse. This enabled them to narrow their search for the mutant gene to
a smaller area. Ultimately, they identified the single-point mutation on
mouse chromosome 11. The normal gene and the shaker-2 gene were nearly
identical except for one DNA base-pair out of more than 30,000 base-pairs
in the gene.

This
is the first permanent correction of a deafness-related genetic mutation
and the fifth time that identification of a deafness gene in mice helped
scientists find a similar gene in humans says Sally A. Camper, associate
professor of human genetics in the University of Michigan Medical School,
who directed the research (pictured).

The single-point mutation occurs in the area coding a gene for a key
enzyme involved in inner ear development. The gene carries coding instructions
for a previously unknown myosin enzyme, now dubbed Myo15.
The researchers believe that one function of this enzyme may be to
transport a protein called actin to inner ear hair cell fibers during their
development. These fibers, or stereocilia, move in response to changes
in sound frequency, sending electrical signals to auditory nerves, which
the brain translates into sound.

In related research, scientists at the National Institute on Deafness
and Other Communication Disorders, National Institutes of Health, report
finding a nearly identical gene (DFNB3) on human chromosome 17, which encodes
the same type of myosin. Mutations in DFNB3 may produce congenital deafness
in humans, just as mutations in shaker-2 do in mice.

"The next step is to develop delivery vehicles to introduce the normal
gene into inner ear cells of individuals who carry these deafness genes,"
said Yehoash Raphael, assistant professor of otolaryngology in the U-M
Medical School, who directed microscopy studies for the project. "Once
adequate vectors are available, gene therapy for genetic-based deafness
will become a reality."